1. Field of the Inventive Concept(s)
The presently disclosed and claimed inventive concept(s) relates generally to compositions useful in target detection and/or treatment, as well as methods of producing and using same.
2. Description of the Background Art
Targeted microbubbles are an important and emerging ultrasound molecular imaging and therapy tool. Many disease states such as but not limited to, cancer, inflammation and thrombosis have unique expression of proteins on the surface of the vascular lumen.
Lanza et al. (1996) describe the sequential delivery of a biotinylated biomarker, avidin, and perfluorocarbon emulsion. In U.S. Pat. No. 7,186,399, Lanza et al. describe an in vivo or in vitro method for ligand-based binding of lipid encapsulated particles to molecular epitopes on a surface. This is accomplished by the sequential delivery of a site specific ligand activated with biotin activating agent, an avidin activating agent, and lipid encapsulated particles activated with a biotin activating agent.
The simultaneous delivery of targeted higher order aggregates of contrast agents has also been described in the literature. These higher order aggregates employ microbubbles, liposomes, nanoparticles, bubble liposomes, liposomal bubbles, nanostructured materials, supramolecular aggregates, quantum dotes, nanotubes, and micelles in various combinations. Many of these particles are multimodal and have therapeutic properties. See for example, Lentacker et al. (2010); Suzuki et al. (2007 and 2008); Myhr et al. (2006); Tinkov et al. (2009); Kheirolomoom et al. (2007); Huang (2008); Kim et al. (2009); Cai et al. (2008); Accardo et al. (2009); Ghaleb et al. (2008); Husseini et al. (2008); Schroeder et al. (2009); McCarthy et al. (2008); U.S. Pat. No. 7,078,015. The entire contents of each of the above-referenced patents and publications are hereby expressly incorporated by reference herein.
Unfortunately, typical adhesion rates of microbubbles retained at the target site are low (on the order of 10 microbubbles per microliter of tissue (Dayton, 2009)), even with the addition of acoustic radiation force. In particular, Dayton (2009) listed the following limitations for targeted contrast agent technology: (1) the low number of contrast agents adherent to a target site; (2) lack of sensitivity to small numbers of contrast agents; and (3) the high background from circulating untargeted contrast. These limitations are discussed in greater detail herein below.
While targeted ultrasound contrast agents demonstrate good specificity to disease, the diagnosis of disease states is limited by the sensitivity attainable by imaging technologies. When contrast agents target specific sites, they are limited to the number of binding sites available on the endothelial surface of the lumen, and therefore one binding site only allows binding of a single microbubble. In addition, the interaction of the microbubble with sites on the endothelial surface is limited by the shear forces created by blood flow through the lumen; thus, the microbubble cannot bind to a surface that it does not “touch” (i.e., with which it comes into contact). Therefore, the prior art methods result in typical binding levels of about 10 microbubbles per microliter.
Further technical limitations of the prior art reside in the imaging equipment: depth and frequency dependent attenuation is seen with ultrasound, and at high power imaging, the high peak negative pressures result in burst microbubbles. In addition, similar depth limitations are seen with other imaging modalities, such as but not limited to, MRI and PET.
Therefore, there is a need in the art for new and improved agents useful in targeted imaging and/or treatment. It is to such compositions, as well as methods of producing and using same, that the presently disclosed and claimed inventive concept(s) is directed.